Safety and tolerability study of clonidine for sedation in mechanically ventilated adult patients

Clonidine is used as an adjunct sedative in mechanically ventilated ICU patients, but prospective data on the safety and tolerability of higher intravenous doses remain limited. This secondary analysis used data from a prospective pharmacokinetic study in 32 critically ill adults. Patients were consecutively enrolled into four dose groups (0, 600, 1200 or 1800 μg/day, 8 per group) and received continuous intravenous clonidine added to standard sedation for up to seven days. Half of the patients in the clonidine groups underwent a four-hour loading phase during which the infusion rate was tripled. Serious adverse events (SAEs), a predefined set of adverse events (AEs), and outcome parameters were recorded. The relatedness of SAEs to clonidine was assessed using the WHO-UMC causality classification system. Patients were monitored for 48 h after clonidine discontinuation. Ten SAEs were reported (3, 3, 3 and 1 in the 0, 600, 1200 and 1800 μg/day dose groups, respectively; Bayes factor (BF) 0.23). Seven SAEs were considered unrelated to clonidine, while three were judged possibly related. No SAEs occurred during the loading phase. No dose-dependent relationship was observed between clonidine dose and bradycardia or hypotension (BF 0.39 and 0.40, respectively). Pleural effusions were more frequent in the control group than in the clonidine groups (BF 12.9). Days on sedation, duration of mechanical ventilation, days in ICU and hospital mortality did not differ between groups. No clinically meaningful tachycardia or hypertension suggestive of clonidine withdrawal was observed. Clonidine was well tolerated within the studied dose range when used as an adjunct to standard sedation in our cohort of non-bradycardic, mechanically ventilated, critically ill adults. No clear dose-dependent increase in predefined adverse events was observed within the studied dose range. These findings provide support for further prospective evaluation of clonidine at doses up to 1800 µg/day in future efficacy studies. ClinicalTrials.gov NCT02466373.